It is well recognized that x-ray radiation is a valuable curative and palliative oncological tool. Radiation therapy is employed for the treatment of many benign and malignant lesions and for organ and bone marrow transplantation modalities.
Although the value of radiation in oncology therapy is universally recognized, the use of high energy radiation in conjunction with chemotherapy is not without its adverse side affects. For example, x-ray radiation has been shown to induce early and/or late radiation-induced skin changes such as skin erythema and ulceration including the severe skin reaction with open blisters, named "moist desquamation" as well as the development of skin cancers.
Up until the 1960's, orthovoltage energies in the range of 150 to 300 kilovolts were used with 100% of the dose delivered to the skin. Doses of x-ray radiation producing skin erythema were used as a quantitative measure as skin reactions were noted to be dose limiting. Today, however, treatment with the electron beam in radiotherapy provides a very high dose to the skin because of rapid dose buildup near the skin surface, compared to earlier megavoltage machines.
It is hypothesized that when tissues are exposed to ionizing radiation, gamma energy is absorbed by water contained within the cells resulting in breakage of the oxygen-hydrogen covalent bonds of the water molecule leaving hydrogen and hydroxyl radicals in situ. It is known that the hydroxyl radical is quite reactive in its interaction with other biomolecules generally thought to be responsible for setting off chain reactions including interactions with the purine and pyrimidine bases of nucleic acids. Many of those who have studied the effects of gamma radiation on the human body believe that radiation-induced cutaneous carcinogenesis may have been initiated by free radical damage. Since radiation often is applied to the human body as a treatment of "deep" lesions such as lung, breast, liver and brain malignancies, it is important to protect the skin from radiation-induced skin damage.
Animals with epithelial tumors have been shown to have increased blood glutathione (GSH) levels. Similarly, higher glutathione levels were detected in groups of humans with disseminated gastric adenocarcinoma and in those with localized or locally advanced skin carcinoma without metastasis. Mean blood GSH levels were 78% and 31% higher, respectively, when compared to control subjects. In blood, most of GSH is present in the red blood cells and may reflect the body's reaction to produce its prime antioxidant, GSH, in response to epithelial malignancies. The rate of generation of GSH within the red blood cells may indicate the body's protective response to reactive species, free radicals, released into plasma by tumors and inflammation.
Antioxidants have been found to inhibit all stages of carcinogenesis whereas other antioxidants are more specific and thus more effective against tumor initiation or promotion and tumor progression. Glutathione and selenium have been shown to play prime roles in protection of carcinogenesis, the latter particularly in skin tumors, when selenium is applied locally as selenomethione or other thiol bonds but also in preventing other cancers, when selenium is taken orally thereby replenishing selenium body stores. Likewise, glutathione, the most abundant tissue thiol and antioxidant, inhibits carcinogenesis, as stated, and indeed when its concentration is suppressed by chemicals so that glutathione levels are significantly lowered, chemical carcinogenesis is enhanced and progression of tumor numbers and tumor size increases. Thus, these studies show the value of glutathione in prevention of tumor formation, making it the ideal antioxidant ingredient along with the other synergistically acting antioxidants in these cosmetic preparations.
The role of intracellular GSH in irradiated cancer cells has been investigated. Reducing the intracellular levels of GSH in tumor cells increases their sensitivity to irradiation or oxidant damage mediated by activated neutrophils or macrophages. Inhibition of GSH synthesis also augments lysis or murine tumor cells by sulfhydryl-reactive anti-neoplastics. Thus, neoplastic cells depleted of their endogenous protective antioxidant, GSH, are more sensitive to radiation damage. Conversely, other studies have shown that increases in intracellular GSH are beneficial. An L-cysteine delivery agent not only enhanced endothelial cell GSH concentration, but also protected these cells in an inverse, linear relationship from damage by endogenous hydrogen peroxide. This preventive role of GSH is of value in treating skin overlying deep areas to be irradiated for cancer but these topical preparations, conversely, are not clinically indicated in the radiotherapy of primary cutaneous neoplasias or malignant skin recurrences.
In the past, attempts to protect the skin from x-ray radiation in oncology therapy has been by a variety of moisturizers and lipid preparations, including aloe vera and mineral oil. However, such compositions have enjoyed little or no success in preventing or healing radiation skin damage.
It is thus an object of the present invention to provide a composition useful in minimizing early as well as late radiation-induced skin changes.
It is yet a further object of the present invention to provide in the form of a topical carrier, certain antioxidants which are effective in reducing radiation-induced cutaneous carcinogenesis which is initiated by the formation of free radicals.
These and further objects will be more readily apparent when considering the following disclosure and appended claims.